Quick viewing(Text Mode)

Chapter 21. Regulation of Calcium and Magnesium

Chapter 21. Regulation of Calcium and Magnesium

SECTION 111 Mineral (Section Editor: Ego Seeman)

21. Regulation of and Magnesium ...... 104 Murray J. Favus and David Goltznian 22. Fetal Calcium ...... 108 Christopher S. Kovacs 23. Fibroblast Growth Factor-23 112

24. Gonadal Steroids ...... 117 Kutrien Venken, Steven Boonen, Roger Bouillon, rind Dirk Vander~schueren 25. ...... 123 Robert A. Nissenson and Harald Jiippner 26. Parathyroid Hormone-Related Protein ...... 127 John J. Wysolmerski 27. Ca*+-SensingReceptor ...... 134 Edward M. Brown 28. : Production, Metabolism, Mechanism of Action, and Clinical Requirements ...... 141 Daniel Bikle, John Adam, and Sylvia Christakos

0 2008 American Society for and Mineral Research 103 Chapter 21. Regulation of Calcium and Magnesium

Murray J. Favusl and David Goltzman’

‘Department of Medicine, University of Chicugo, Chicugo, Illinois; ”Center for Advanced Bone and Periodontul Research, McCill University, Montreul, Quebec, Chnrirlu

CALCIUM hancing it. Consequently major shifts in serum protein or pH requires direct measurement of the ionized Ca level to deter- Distribution mine the physiologic serum calcium level. Total Body Distribution. In adults, the body contains -1000 g of Ca, of which 99% is located in the mineral phase of bone as Mineral Homeostasis the crystal [Ca,,,(PO,),(OH),]. The crystal The ECF concentration of calcium is tightly maintained plays a key role in the mechanical weight-bearing properties of within a rather narrow range because of the importance of the bone and serves as a ready source of Ca to support a number Ca ion to numerous cellular functions including cell division, of Ca-dependent biological systems and to maintain blood ion- cell adhesion and plasma membrane integrity, protein secre- ized Ca within the normal range. The remaining 1% of total tion. , neuronal excitability, glycogen me- body Ca is located in the blood, , and soft tabolism, and . tissues. In serum, total Ca is lo-’ M and is the most frequent The skeleton, the gut, and the each plays a major role measurement of serum Ca levels. Of the total Ca, the ionized in assuring Ca homeostasis. Overall, in a typical individual, if fraction (50%) is the biologically functional portion of total Ca 1000 mg of Ca is ingested in the diet per day, -200 mg will be and can be measured clinically; 40% of the total is bound to absorbed. Approximately 10 g of Ca will be filtered daily albumin in a pH-dependent manner; and the remaining 10% through the kidney, and most will be reabsorbed, with -200 mg exists as a complex of either citrate or PO, ions. being excreted in the urine. The normal 24-h excretion of Ca Cell Levels. Ca is -10-‘ M, which creates a 1000-fold may, however, vary between 100 and 300 mg/d (2.5-7.5 mmol/ gradient across the plasma membrane (extracellular fluid d). The skeleton, a storage site of -1 kg of Ca, is the major Ca [ECF] Ca is lo-’ M) that favors Ca entry into the cell. There reservoir in the body. Ordinarily, as a result of normal bone is also an electrical charge across the plasma membrane of -50 turnover, -500 mg of Ca is released from bone per day, and the mV with the cell interior negative. Thus, the chemical and equivalent amount is accreted per day (Fig. 1). electrical gradients across the plasma membrane favor Ca en- Tight regulation of the ECF calcium concentration is main- try, which the cell must defend against to preserve cell viability. tained through the action of Ca-sensitive cells that modulate Ca-induced cell death is largely prevented by several mecha- the production of These hormones act on spe- nisms including extrusion of Ca from the cell by ATP- cific cells in bone, gut, and kidney, which can respond by al- dependent energy driven Ca pumps and Ca channels; Na-Ca tering fluxes of Ca to maintain ECF Ca. Thus, a reduction in exchangers; and binding of intracellular Ca by proteins located ECF Ca stimulates release of PTH from the parathyroid glands in the cytosol, (ER), and mitochondria. in the neck. This hormone can act to enhance bone resorption Ca binding to ER and mitochondria1 sites buffer intracellular and liberate both Ca and from the skeleton. FTH Ca and can be mobilized to maintain cytosol Ca levels and to can also enhance Ca reabsorption in the kidney while at the create pulsatile peaks of Ca to mediate membrane receptor same time inhibit phosphate reabsorption producing phospha- signaling that regulate a variety of biological systems. turia. and PTH itself can both stimulate the conversion of the inert metabolite of vitamin D, 25- Blood Levels. Ca in the blood is normally transported partly hydroxyvitamin D, [25(OH)D,] to the active moiety 1,25- bound to plasma proteins (-45%), notably albumin, partly dihydroxyvitamin D, [1,25(OH),D,],‘”’ which in turn will en- bound to small anions such as phosphate and citrate (-10Y0), hance intestinal Ca absorption, and to a lesser extent, renal and partly in the free or ionized state (-45%).“’ Although only phosphate reabsorption. The net effect of the mobilization of the ionized Ca is available to move into cells and activate Ca from bone, the increased absorption of Ca from the gut, cellular processes, most clinical laboratories report total serum and the increased reabsorption of filtered Ca along the neph- Ca concentrations. Concentrations of total Ca in normal serum ron is to restore the ECF Ca to normal and to inhibit further generally range between 8.5 and 10.5 mg/dl (2.12-2.62 mM), production of PTH and 1,25(OH),D,. The opposite sequence and levels above this are considered to be hypercalcemic. The of events [i.e., diminished PTH and 1,25(OH),D, secretion], normal range of ionized Ca is 4.65-5.25 mgidl (1.16-1.31 mM). along with Stimulation of renal Ca sensing receptor (CaSR), When protein concentrations, and especially albumin concen- occurs when the ECF Ca is raised above the normal range. The trations, fluctuate, total Ca levels may vary, whereas the ion- effect of suppressing the release of PTH and 1,25(OH),D, and ized Ca may remain relatively stable. Dehydration or hemo- stimulating CaSR diminishes skeletal Ca release, decreases in- concentration during venipuncture may elevate testinal Ca absorption and renal Ca reabsorption, and restores and falsely elevate total serum Ca. Such elevations in total Ca, the elevated ECF Ca to normal. when albumin levels are increased, can be “corrected” by sub- tracting 0.8 mg/dl from the total Ca for every 1.0 gidl by which PTH and 1,25(OH),D, Actions on Target Tissues the serum albumin concentration is >4 g/dl. Conversely, when Intestinal Ca Transport. Net intestinal Ca absorption can be albumin levels are low, total Ca can be corrected by adding 0.8 determined by the external balance technique in which a diet mg/dl for every 1.0 g/dl by which the albumin is <4 g/dl. Even of known composition with a known amount of Ca is ingested, in the presence of a normal serum albumin, changes in blood and urine Ca excretion and fecal Ca loss are measured. Nega- pH can alter the equilibrium constant of the albumin-Ca2’ tive absorption occurs when net absorption declines to -200 complex, with acidosis reducing the binding and alkalosis en- mg Ca/d (5.0 mmol). The portion of dietary Ca absorbed varies with age and amount of Ca ingested and may vary from 20% The authors state that they have no conflicts of interest to 60%. Rates of net Ca absorption are high in growing chil-

104 0 2008 American Society for Bone and Mineral Research REGUL.ATIONOF CALCIUM AND MAGNESIUM/ 105

FIG. 1. Calcium balance. On average, in a typical adult, -1 g of elemental calcium (Ca+') is ingested per day. Of this, -200 mg/d will be absorbed and 800 mgid excreted. Approximately 1 kg of Ca is stored in bone and -SO0 mgid is released by resorption or deposited during bone formation. Of the 10 g of Ca filtered through the kidney per day, only -200 mg or less ap- pears in the urine, the remainder being reabsorbed. dren; during grow spurts in adolescence; and during pregnancy Renal Ca Handling. The kidney plays a central role in ensur- and lactation. The efficiency of Ca absorption increases during ing Ca balance, and PTH has a major role in fine-tuning this prolonged dietary Ca restriction to absorb the greatest portion renal function("'-l2) by stimulating both renal Ca reabsorption of that ingested. Net absorption declines with age in men and (proximal tubule) and excretion (distal nephron). Multiple in- women, and so increased Ca intake is required to compensate fluences of Ca handling are listed in Table 2. Descriptions of for the lower absorption rate. Fecal Ca losses vary between 100 the molecular actions of PTH on the kidney are found else- and 200 mg/d (2.5-5.0 mmol). Fecal Ca is composed of unab- where in the Primer. PTH has little effect on modulating Ca sorbed dietary Ca and Ca contained in intestinal, pancreatic, fluxes in the proximal tubule where 65% of the filtered Ca is and biliary secretions. Secreted Ca is not regulated by hor- reabsorbed, coupled to the bulk transport of solutes such as mones or serum Ca. and water.'") In this nephron region, PTH can also Because of the large surface area of the and stimulate the 25(OH)D,-la hydroxylase la(OH)ase], leading jejunum, 90% of absorbed Ca occurs in these regions. In- to increased synthesis of 1,25(OH),D,.(13 I A reduction in ECF creased Ca requirements stimulate expression of the epithelial Ca can itself stimulate 1,25(OH),D, production but whether cellular Ca system in duodenum, , and this occurs through the CaSR is presently unknown. Finally throughout the colon sufficient to increase fractional Ca ab- PTH can also inhibit Na and HC0,- reabsorption in the proxi- sorption from 2045% in older men and women to 55-70% in mal tubule by inhibiting the apical type 3 Na'lH' e~changer"~) children and young adults.l,25(OH),D3 increases the effi- and the basolateral Na'/K'-ATPase'lS' by inhibiting apical ciency of the small intestine and colon to absorb dietary Ca. Na'/Pi ~ cotransport. Active Ca absorption accounts for absorption of 1Ok15% of a About 20% of filtered Ca is reabsorbed in the cortical thick dietary load.(') Active transcellular intestinal absorption in- ascending limb of the loop of Henle (CTAL) and 15% is re- volves three sequential cellular steps: a rate-limiting step in- absorbed in the distal convoluted tubule (DCT). At both sites, volving transfer of luminal Ca into the intestinal cell through PTH binds to the PTH receptor (PTHR)'".") and enhances the epithelial Ca channel, expression of TRPV6, a channel- Ca reabsorption. In the CTAL, at least, this seems to occur by associated protein, annexin2, and -D9K, and to a lesser extent, the basolateral extrusion system PMCAl Reductions in dietary Ca intake can increase PTH secretion TAI3L.E 1. CONDITIONS THATINCREASE OK DEC-RFASEINTESTINAL and 1,25(OH),D, production, which can enhance fractional Ca CA ABSOKPTION absorption and compensates for the dietary reduction. Intestinal epithelial Ca transport includes both an energy- Iiicreami Cu UhWr[JtlOn Decreused Cu absorption dependent, cell-mediated saturable active process that is Increased renal 1,2S(OH),D, Decreased renal 1,2S(OH),D, largely regulated by 1,25(OH),D,, and a passive, diffusional production production paracellular path of absorption that is driven by transepithelial Growth Vitamin D deficiency electrochemical gradients. The cell-mediated pathway involv- Pregnancy Chronic renal insufficiency ing the TRPV6 Ca channel is saturable with a Kt (1/2 maximal Lactation Hypoparathyroidism transport) of 1.0 mM. Passive diffusion increases linearly with Primary hyper1,arathyroidism Vitamin D-dependent luminal Ca concentration and is not regulated by 1,25(OH),D,. Idiopathic hypercalciuria type 1 In adults fed a diet low in Ca, enhanced 1,25(OH),D, produc- Increased extrarenal 1 ,2S(OH)2D3 Aging tion increases the efficiency of absorption through an increase production Normal 1,2S(OH),D, in saturable Ca transport. During high dietary Ca intake ab- Sarcoid and other granulomatous production sorption, 1,25(OH),D, is suppressed and passive paracellular diseases Glucocorticoid excess transport accounts for most all absorption. Causes of increased B-cell lymphoma Hyperthyroidism and decreased intestinal Ca absorption are listed in Table 1.

0 2008 American Society for Bone and Mineral Research TABLE2. HORMONESAND CONDITIONS THAT REGULATEURINE CA AND Mediators of . Calcitropic hormones PTH, MG EXCRETION PTH-related peptide (PTHrP), and 1,25(OH),D, initiate os- teoclastic bone resorption and increase the activation fre- Hormonedconditions Calcium Magnesium quency of bone remodeling. Physiologic control of bone turn- Hypercalcemia 1 D over can be disrupted by an excess of each of these calcitropic H ypocalcemia D I hormones, resulting in altered ECF Ca homeostasis and hy- Hypermagnesemia - I percalcemia. The molecular basis for physiologic and patho- Hypomagnesemia D D logic states of bone turnover is detailed elsewhere in the Renal insufficiency D D Primer. Tubular reabsorption Increased Regulation of Hormone Production and Actions on Ca ECF volume contraction I Homeostasis H ypocalcemia I Thiazide diuretics - PTH Production. A major regulator of se- Phosphate administration I cretion of PTH is ECF Ca. The relationship between ECF Ca Metabolic alkalosis I and PTH secretion is governed by a steep inverse sigmoidal Parathyroid hormone I curve which is characterized by a maximal secretory rate at low Parathyroid hormone related peptide I ECF Ca, a midpoint or “set point,” which is the level of ECF Familial hypocalciuric hypercalcemia - Ca, which half-maximally suppresses PTH, and a minimal se- Decreased cretory rate at high ECF Ca.(21-22)The parathyroid glands de- ECF volume expansion D tect ECF Ca through a CaSR.(23)Sustained hypocalcemia can Hypercalcemia D eventually lead to parathyroid cell pr~liferation‘~~’and an in- Phosphate deprivation D creased total secretory capacity of the parathyroid gland. Metabolic acidosis - 1,25(OH) D, reduces PTH synthesis and parathyroid cell pro- Loop diuretics D liferatior~?’~)Molecular events in PTH secretion and CaSR Cyclosporin A D function are found elsewhere in the Primer. Autosomal dominant hypocalcemia - Dent’s disease Vitamin D Production and Actions. The renal production of Bartter’s syndrome - 1,25(OH),D, is stimulated by hypocalcemia, hypophosphate- Gittelman’s syndrome D mia and elevated PTH levels. The renal la(0H)ase is also potently inhibited by 1,25(OH),D, as part of a negative feed- D, decreased GFR or tubule reabsorption; 1, increased GFR or tubule reab- back loop. The molecular details of the vitamin D metabolic sorption; -, either modest effects are present or that no specific information is pathway are described elsewhere in the Primer. available. Vitamin D is essential for normal mineralization of bone that may be caused by an indirect effect by enhancing intesti- nal calcium and phosphate absorption and maintaining these increasing the activity of the Na/K/2 C1 co-transporter that ions within a range that facilitates hydroxyapatite deposition in drives NaCl reabsorption and stimulates paracellular Ca and bone matrix. A major indirect function of 1,25(OH),D, on Mg reabsorption.(’8) The CaSR is also resident in the bone seems to be to enhance mobilization of Ca stores when CTAL,(l9)where increased ECF Ca activates phospholipase dietary Ca is insufficient to maintain a normal ECF Ca.(”) As A2, thereby reducing the activity of the NalKI2CI co- with PTH,‘”) 1.25(OH),D3 enhances osteoclastic bone resorp- transporter and of an apical K channel and diminishing para- tion by binding to receptors in the pre-osteoblastic stromal cell cellular Ca reabsorption. Consequently, a raised ECF Ca an- and stimulating the RANK/RANK system to enhance the pro- tagonizes the effect of PTH in this nephron segment and ECF liferation, differentiation, and activation of the osteoclastic sys- Ca can in fact participate in this way in the regulation of its tem from its monocytic precursors.(28)Endogenous and exog- own homeostasis. Inhibition of NaCl reabsorption and loss of enous 1,25(OH),D3 have also been reported to have an NaCl in the urine may contribute to the volume depletion anabolic role in ~ivo.(~’~~”)1,25(OH),D, has a direct effect on observed in severe hypercalcemia. ECF Ca may therefore act renal Ca handling through stimulation of CaSR. It remains in a manner analogous to “loop” diuretics such as furosemide. controversial whether 1,25(OH),D, plays a direct role in en- In the DCT, PTH can also influence(’) luminal Ca transfer hancing tubular Ca reabsorption. into the renal tubule cell through the transient receptor poten- tial channel (TRPVS), translocation of Ca across the cell from apical to basolateral surface involving proteins such as calbin- MAGNESIUM din-D28K, and finally active extrusion of Ca from the cell into Total Body Distribution the blood through an Na’iCa exchanger, designated NCX1. PTH markedly stimulates Ca reabsorption in the DCT primar- There is -1.04 mol (25 g) of Mg in the adult, of which -66% ily by augmenting NCXl activity through a cyclic AMP- is within the skeleton, 33% is intracellular, and 1% is in the mediated mechanism. ECF including blood.(’.2’ Mg content of the hydroxyapatite crystal in bone varies widely and is mainly on the surface of Bone Resorption and Ca Release. In bone, the PTHR is lo- bone where a portion is in equilibrium with ECF Mg. Mg is the calized on cells of the phenotype that are of mes- most abundant divalent cation within cells, where it is found at enchymal origin‘2”’ but not on that are of hema- a concentration of -5 x M in the cytosol. In the cells, it togenous origin. The major physiologic role of PTH seems to serves as a co-factor and regulates a number of essential bio- be to maintain normal Ca homeostasis by enhancing osteoclas- logical systems.‘” The concentration of Mg in the ECF ap- tic bone resorption and liberating Ca into the ECF. Bone for- proaches that of the intracellular environment. Both intracel- mation and resorption are discussed in detail elsewhere in the lular and ECF are tightly regulated by factors that are poorly Primer. understood.

0 2008 American Society for Bone and Mineral Research REC~JLATIONOF CALCIUM AND MAGNESIUM/ 107

Cellular Content convoluted tubule and may be involved in Mg homeostasis in both the kidney and intestine. Ionic cytosolic Mg accounts for 5-10% of total cellular Mg. Cytosol Mg is regulated by binding to intracellular organelles, REFERENCES of which 60% is within mitochondria where it participates in phosphate transport and ATP utilization. Control of intracel- 1. Walser M 1961 Ion association: VI. Interactions between calcium, Mar Mg is poorly understood. magnesium, inorganic phosphate. citrate, and protein in normal human plasma. J Clin Invest 40:723-735. 2. Parfitt AM, Kleerekoper M 1980 Clinical disorders of calcium, Homeostasis and magnesium metabolism. In: Maxwell MH, Klee- man CR (eds.) Clinical Disorders of Fluid and Me- Of the total serum Mg, 70% is either ionic or complexed, tabolism. 3rd ed. McGraw-Hill, New York, NY, USA, pp. 947- and the remaining 30% is protein bound.(’.*) Blood levels are 1151. not as tightly regulated as Ca but fluctuate with influx and 3. Stewart AF, Broadus AE 1987 Mineral metabolism. In: Felig P, efflux across the ECF with changes in intestinal Mg absorption, Baxter ID. Broadus AE, Frohman LA (eds.) and net renal Mg reabsorption, and influx and efflux across bone. Metabolism, 2nd ed. McGraw-Hill, New York, NY, USA, pp. 13 17-1 453. Blood ionic Mg regulates PTH secretion, but the potency is 4. Bringhurst FR, Demay MB, Kronenberg HM 1988 Hormones and less than that of Ca. disorders of mineral metabolism. In: Wilson JD, Foster DW, Kro- nenberg HM, Larsen PR (eds.) Williams Textbook of Endocrinol- Intestinal Absorption ogy, 9th ed. Saunders, Philadelphia, PA, USA, pp. 1155-1209. 5. Brown EM 2001 of calcium homeostasis. In: Bilezikian Mg is a requirement for bone health; however, unlike Ca, JP, Marcus R, Levine MA (eds.) The Parathyroids: Basic and Mg is found in all food groups and is especially rich in foods of Clinical Concepts, 2nd ed. Academic Press, San Diego. CA, USA. pp. 167-181. cellular origin. Therefore, Mg deficiency caused by inadequate 6. Fraser DR, Kodicek E 1973 Regulation of 25-hydroxychole- intake does not occur in the absence of severe defects in in- calciferol-1-hydroxylaseactivity in kidney by parathyroid hor- testinal or renal function. Net intestinal Mg absorption is in mone. Nat New Biol 241:163-166. direct proportion to dietary Mg ingestion. Under conditions of 7. Favus MF 1992 Intestinal absorption of calcium, magnesium and stable Mg intake, external Mg balance studies show that when phosphorus. In: Coe FL, Favus MJ (eds.) Disorders of Bone and Mineral Metabolism. Raven, New York, NY, USA, pp. 57-81. Mg intake is >28 mg (2 mmol), Mg absorption exceeds Mg 8. Hoenderop JGJ, Nilius B, Bindels RJM 2005 Calcium absorption secretion, and Mg balance becomes positive. The efficiency of across epithelia. Physiol Rev 85:373422. Mg absorption is 3540% over the range of usual intakes (168- 9. Van de Ciraaf SFJ, Boullart I, Hoenderop JGJ, Bindels RJM 2004 720 mg/d or 7-30 mmol). Net Mg absorption also varies with Regulation of the epithelial Ca” channels TRPVS and TRPV6 by dietary constituents such as phosphate, which forms insoluble la,25-dihydroxy Vitamin D3 and dietary Ca”. J Steroid Biochem complexes with Mg and thereby reduces Mg absorption. In Mol Biol 89-90:303-308. 10. Friedman PA, Gesek FA 1995 Cellular calcium transport in renal contrast to its actions on Ca and P absorption, 1,25(OH),D, epithelia: Measurement, mechanisms, and regulation. Physiol Rev does not stimulate Mg absorption. There is no correlation be- 15:42947 1. tween serum 1,25(OH),D, levels and net Mg absorption.(”) 11. Nordin BE, Peacock M 1969 Role of kidney in regulation of Absorptive and secretory Mg fluxes across both small intes- plasma-calcium. Lancet 2:1280-1283. tine and colon are largely voltage dependent, indicating the 12. Rouse D. Suki WN 1990 Renal control of extracellular calcium. presence of a large paracellular pathway of Mg transport that Kidney Int 38:70%708. 13. Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, is driven by luminal Mg concentrations. The Mg ion channel Anazawa H. Suda T. DeLuca HF 1998 Parathyroid hormone ac- TRPM6 has been identified in the apical membrane of intes- tivation of the 25-hydroxyvitamin D3-la-hydroxylase gene pro- tinal brush border epithelial cells that seems to play an impor- moter. Proc Natl Acad Sci USA 951387-1391. tant role in Mg homeostasis.(”) Whether TRPM6 is regulated 14. Azarani A. Goltzman D, Orlowski J 1995 Parathyroid hormone by PTH or 1,25(OH),D, has yet to be determined. and parathyroid hormone-related peptide inhibit the apical Na+/ H+ exchanger NHE-3 isoform in renal cells (OK) via a dual sig-

naling cascade involvinevL urotein kinase A and C. J Biol Chem Renal Handling 270:%004-20010. 15. Derrickson BH. Mandel LJ 1997 Parathyroid hormone inhibits Ultrafiltrable Mg is 70% of the total serum Mg (ionized plus Na(+)-K(+)-ATPase through GqiGi 1 and the calcium- complexed). Based on the urine Mg excretion (-24 mmo1124 independent phospholipase A2. Am J Physiol 272:F781-F788. h), -95% of the filtered load of Mg undergoes tubular reab- 16. Juppner H, Abou-Samra AB, Freeman MW, Kong XF, Schipani sorption before the final urine is formed. A small fraction of E, Richards J, Kolakowski LF Jr, Hock J, Potts JTJr, Kronenberg reabsorbed Mg (15%0) occurs along the proximal tubule, HM. Segre GVA 1991 G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science whereas -70% of filtered Mg is reabsorbed along the cortical 254: 1024-1026. TALH.(’X.”2)Mg ion may also stimulate basolateral membrane 17. Abou-Samra AB, Juppner H, Force T, Freeman MW, Kong XF, CaR, which decreases renal Mg reabsorption. DCT Mg reab- Schipani E, Urena P. Richards J, Bonventre JV, Potts JT Jr, Kro- sorption is through a transcellular transport process and ac- nenberg HM, Segre GV 1992 Expression cloning of a common counts for -10% of Mg reabsorption. receptor for parathyroid hormone and parathyroid hormone- Mg reabsorption is highly regulated, with a number of fac- related peptide from rat osteoblast-like cells: A single receptor stimulates intracellular accumulation of both CAMP and inositol tors that may increase or decrease renal tubule Mg reabsorp- triphosphates and increases intracellular free calcium. Proc Natl tion (Table 2). Because there is little distal tubule Mg reab- Acad Sci USA 89:2732-2736. sorption, ECF volume expansion decreases Mg reabsorption 18. De Rouffignac C, Quamme GA 1994 Renal magnesium handling and increases urine Mg excretion. Hypermagnesemia increases and its hormonal control. Physiol Rev 74:305-322. urine Mg excretion at least in part through an activation of 19. Hebert SC 1996 Extracellular calcium-sensing receptor: Implica- CaR.(”) In contrast, hypomagnesemia increases TALH Mg tions for calcium and magnesium handling in the kidney. Kidney Int 50:2129-2 139. reabsorption and decreases urine Mg excretion. Loop diuretics 20. Rouleau MF, Mitchell J, Goltzman D 1988 In vivo distribution of increase urine Mg excretion, and thiazide diuretic agents have parathyroid hormone receptors in bone: Evidence that a predomi- a minimal effect of Mg transport (Table 2). The Mg ion chan- nant OSS~OUStarget cell is not the mature osteoblast. Endocrinol- nel TRPM6 is found in the apical membrane of the renal distal ogy 123:187-191.

0 2008 American Society for Bone and Mineral Research 108 / CHAP~ER~~

21. Potts JT Jr, Juppner H 1997 Parathyroid hormone and parathyroid 27. Lee SK, Lorenzo JA 1999 Parathyroid hormone stimulates hormone-related peptide in calcium homeostasis, bone metabo- TRANCE and inhibits osteoprotegerin messenger ribonucleic acid lism, and bone development: The proteins, their genes, and recep- expression in niurine bone marrow cultures: Correlation with os- tors. In: Avioli LV, Krane SM (eds.) Metabolic Bone Disease, 3rd teoclast-like cell formation. Endocrinology 140:3552-3561. ed. Academic Press, New York, NY, USA, pp. 51-84. 28. Takahashi N, Udagawa N, Takami M, Suda T 2002 Cells of bone: 22. Grant FD, Conlin PR, Brown EM 1990 Rate and concentration gencration. In: Bilezikian JP, Raisz LG, Rodan GA dependence of parathyroid hormone dynamics during stepwise (eds.) Principles of bone biology, 2nd ed. Academic Press, San changes in serum ionized calcium in normal humans. J Clin En- Diego, CA, USA, pp. 109-126. docrinol Metab 71:370-378. 29. Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman 23. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor D 2004 Inactivation of the 25-dihydroxyvitamin D-lalpha- 0, Sun A, Hediger MA, Lytton J. Hebert SC 1993 Cloning and hydroxylase and vitamin D receptor demonstrates independent characterization of an extracellular Ca(2+)-sensing receptor from effects of calcium and vitamin D on skeletal and mineral homeo- bovine parathyroid. Nature 366575-580. stasis. J Biol Chem 279:16754-16766. 24. Kremer R, Bolivar 1. Goltzman D, Hendy GN 1989 Influence of 30. Xue Y, Karaplis AC, Hendy GN, Goltzman D, Miao D 2006 Ex- calcium and 1,2S-dihydroxycholecaIcifcrol on proliferation and ogenous 1,2S-dihydroxyvitamin D3 exerts a skeletal anabolic ef- proto-oncogene expression in primary cultures of bovine parathy- fect and improves mineral ion homeostasis in mice which are ho- roid cells. Endocrinology 125:935-941. mozygous for both the l(alpha) hydroxylase and parathyroid 25. Goltzman D, Miao D, Panda DK, Hendy GN 2004 Effects of hormone null alleles. Endocrinology 147:48014810. calcium and of the vitamin D system on skeletal and calcium ho- 31. Schmulen AC. Lenian M, Pak CY, Zerwekh J, Morawski S, meostasis: Lessons from genetic models. J Steroid Biochern Mol Fordtran JS. Vergne-Marini P 1980 Effect of 1,2S(OH),D, on je- Biol 89-90:485-489. junal absorption of magnesium in patients with chronic renal dis- 26. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R. ease. Am J Physiol 238:G349-G351. Demay MB 1997 Targeted ablation of the vitamin D receptor: 32. Yu ASL 2004 Renal transport of calcium, magnesium, and phos- An animal model of vitamin D-dependent rickets type I1 with phate. In: Brenner BM (ed.) The Kidney, 7th ed. Saunders, Phila- alopecia. Proc Natl Acad Sci USA 9439831-9835. delphia, PA, USA. pp. 535-572.

Chapter 22. Fetal Calcium Metabolism

Christopher S. Kovacs

Faculty of Medicine-Endocrinology, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada

INTRODUCTION serum magnesium is minimally elevated above the maternal concentraGon. The physiological importance of these elevated Much of normal mineral and bone homeostasis in the adult can levels is not known; complete mineralization of the skeleton be explained by the interactions of PTH. 1,25-dihydroxy- vitamin D or (1,25-D), . and the sex ste- and survival to term have been noted in genetically manipu- roids. In contrast, comparatively little is known about how lated mice in which the fetal blood calcium is not raised above mineral and bone homeostasis is regulated in the fetus. Be- the maternal level. The normal increase in the fetal calcium cause of obvious limitations in studying human fetuses, human level is robustly maintained despite maternal hypocalcemia regulation of fetal mineral homeostasis must be largely in- from a variety of causes. For example, adult humans and mice ferred from studies in animals, and some observations in ani- with nonfunctional vitamin D receptors (VDRs) are hypocal- mals may not apply to humans. This chapter briefly reviews cemic, but Vdr-null fetuses have normal serum calcium con- existing human and animal data; for more information and centrations.(3' references, the reader is referred to two comprehensive re- Calcitropic hormone levels are also maintained at levels that views on the subject.".2' differ from the adult. These differences seem to reflect the Fetal mineral metabolism has been adaptcd to maintain an relatively different roles that these hormones play in the fetus extracellular level of calcium (and other minerals) that is and are not an artifact of altered metabolism or clearance of physiologically appropriate for fetal tissues and to provide suf- these hormones. Intact PTH levels are much lower than ma- ficient calcium (and other minerals) to fully mineralize the ternal PTH levels near the end of gestation, but it is unknown skeleton before birth. Mineralization occurs rapidly in late ges- whether fetal PTH levels are low throughout gestation after tation, such that a human accretes 80% of the required 30 g of the formation of the parathyroids or only in late gestation. calcium in the third trimester, whereas a rat accretes 95% of Despite its low level, PTH is important for fetal development the required 12.5 mg of calcium in the last 5 days of its 3-wk because fetal mice lacking parathyroids or PTH are hypocal- gestation. cemic and have undermineralized skeletons.(4-"' Circulating 1.25-D levels are also lower than the maternal level in late gestation and seem to he largely if not completely derived from MINERALS IONS AND CALCIOTROPIC fetal sources. The low circulating levels of 1,25-D in the fetus HORMONES may be a response to high serum phosphate and low PTH. 1,25-D may also be relatively unimportant for fetal mineral A consistent finding among human and other mammalian fetuses is a total and ionized calcium concentration that is significantly higher than the maternal level during late gesta- Key words: tetus, pregnancy, calcium, magnesium, phosphorus, tion. Similarly, serum phosphate is significantly elevated, and PTH, PTH-related protein, calcitonin, vitamin D, calcitriol, estradiol, hyperparathyroidisni, hypoparathyroidism, familial hypocalciuric hy- percalcemia, vitamin D deficiencyiinsufficiency, placenta, placental The author states that he has no conflicts of interest. calcium transport, calcium receptor, rickets

0 2008 American Society for Bone and Mineral Research

Top View